{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T01:51:43Z","timestamp":1773971503704,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,12]]},"group-title":"Cell Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background &amp; Aims<\/jats:title>\n                  <jats:p>\n                    Mitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene name\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    ), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    Flox\/Flox (\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    <jats:sup>F\/F<\/jats:sup>\n                    ),\n                    <jats:italic>Mfn1<\/jats:italic>\n                    <jats:sup>F\/F<\/jats:sup>\n                    and\n                    <jats:italic>Mfn2<\/jats:italic>\n                    <jats:sup>F\/F<\/jats:sup>\n                    mice were crossed with albumin-Cre mice to generate liver-specific\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    knockout (L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO), L-\n                    <jats:italic>Mfn1<\/jats:italic>\n                    KO, L-\n                    <jats:italic>Mfn2<\/jats:italic>\n                    KO, L-\n                    <jats:italic>Mfn1, Mfn2<\/jats:italic>\n                    double KO (DKO), and L-\n                    <jats:italic>Mfn1, Mfn2, Dnm1l<\/jats:italic>\n                    triple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system with\n                    <jats:italic>c-MYC<\/jats:italic>\n                    and\n                    <jats:italic>YAP<\/jats:italic>\n                    . Blood and liver tissues were harvested for biochemical and histological analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice also developed liver tumors, their incidence was much lower.\n                  <\/jats:p>\n                  <jats:p>\n                    In contrast, neither L-\n                    <jats:italic>Mfn1<\/jats:italic>\n                    KO nor L-\n                    <jats:italic>Mfn2<\/jats:italic>\n                    KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice but were less evident in L-\n                    <jats:italic>Mfn1<\/jats:italic>\n                    KO, L-\n                    <jats:italic>Mfn2<\/jats:italic>\n                    KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion of\n                    <jats:italic>Mfn1<\/jats:italic>\n                    and\n                    <jats:italic>Mfn2<\/jats:italic>\n                    in L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L-\n                    <jats:italic>Dnm1l<\/jats:italic>\n                    KO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.11.637688","type":"posted-content","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T12:35:22Z","timestamp":1739363722000},"source":"Crossref","is-referenced-by-count":2,"title":["Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis"],"prefix":"10.64898","author":[{"given":"Xiaowen","family":"Ma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengwei","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheyun","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junrong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyang","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaolei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Sesaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Xing","family":"Zong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong-Min","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Xing","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025021410201190000_2025.02.11.637688v1.1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.3055"},{"key":"2025021410201190000_2025.02.11.637688v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.10.014"},{"issue":"3","key":"2025021410201190000_2025.02.11.637688v1.3","doi-asserted-by":"crossref","first-page":"S118","DOI":"10.1016\/j.ijrobp.2018.06.295","article-title":"Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response","volume":"102","year":"2018","journal-title":"International Journal of Radiation Oncology Biology Physics"},{"key":"2025021410201190000_2025.02.11.637688v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0772-z"},{"key":"2025021410201190000_2025.02.11.637688v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(19)31518-5"},{"key":"2025021410201190000_2025.02.11.637688v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.10.014"},{"key":"2025021410201190000_2025.02.11.637688v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.12.002"},{"key":"2025021410201190000_2025.02.11.637688v1.8","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2921"},{"key":"2025021410201190000_2025.02.11.637688v1.9","doi-asserted-by":"crossref","unstructured":"Dai, W. , J. Shen , J. Yan , A. J. Bott , S. Maimouni , H. Q. Daguplo , Y. Wang , K. Khayati , J. Y. Guo , L. Zhang , Y. Wang , A. Valvezan , W. X. Ding , X. Chen , X. Su , S. Gao and W. Zong (2022). \u201cGlutamine synthetase limits beta-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.\u201d J Clin Invest 132(24).","DOI":"10.1172\/JCI161408"},{"key":"2025021410201190000_2025.02.11.637688v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00524-z"},{"key":"2025021410201190000_2025.02.11.637688v1.11","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065X.2002.18802.x"},{"key":"2025021410201190000_2025.02.11.637688v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature24050"},{"key":"2025021410201190000_2025.02.11.637688v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.06.007"},{"key":"2025021410201190000_2025.02.11.637688v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3586"},{"key":"2025021410201190000_2025.02.11.637688v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.04.010"},{"key":"2025021410201190000_2025.02.11.637688v1.16","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780090710"},{"key":"2025021410201190000_2025.02.11.637688v1.17","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1166318"},{"key":"2025021410201190000_2025.02.11.637688v1.18","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201488658"},{"key":"2025021410201190000_2025.02.11.637688v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.01.002"},{"key":"2025021410201190000_2025.02.11.637688v1.20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0761"},{"key":"2025021410201190000_2025.02.11.637688v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.98"},{"key":"2025021410201190000_2025.02.11.637688v1.22","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010245"},{"key":"2025021410201190000_2025.02.11.637688v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27699-2"},{"key":"2025021410201190000_2025.02.11.637688v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-020-0191-6"},{"key":"2025021410201190000_2025.02.11.637688v1.25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708857"},{"key":"2025021410201190000_2025.02.11.637688v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32604"},{"key":"2025021410201190000_2025.02.11.637688v1.27","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040963"},{"key":"2025021410201190000_2025.02.11.637688v1.28","first-page":"1","article-title":"Perspectives of mitochondria-lysosome-related organelle in hepatocyte dedifferentiation and implications in chronic liver disease","volume":"2","year":"2024","journal-title":"eGastroenterology"},{"key":"2025021410201190000_2025.02.11.637688v1.29","doi-asserted-by":"crossref","unstructured":"Ma, X. , M. Niu , H. M. Ni and W. X. Ding (2024). \u201cMitochondrial dynamics, quality control, and mtDNA in alcohol-associated liver disease and liver cancer.\u201d Hepatology.","DOI":"10.1097\/HEP.0000000000000910"},{"issue":"5","key":"2025021410201190000_2025.02.11.637688v1.30","first-page":"1278","article-title":"The role of mitochondrial dynamics in human cancers","volume":"10","year":"2020","journal-title":"Am J Cancer Res"},{"key":"2025021410201190000_2025.02.11.637688v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv468"},{"key":"2025021410201190000_2025.02.11.637688v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24690"},{"key":"2025021410201190000_2025.02.11.637688v1.33","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30770"},{"key":"2025021410201190000_2025.02.11.637688v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2014.11.006"},{"key":"2025021410201190000_2025.02.11.637688v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2014.11.006"},{"key":"2025021410201190000_2025.02.11.637688v1.36","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1972"},{"key":"2025021410201190000_2025.02.11.637688v1.37","first-page":"572","article-title":"Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome","volume":"12","year":"2020","journal-title":"Sci Transl Med"},{"key":"2025021410201190000_2025.02.11.637688v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.02.019"},{"key":"2025021410201190000_2025.02.11.637688v1.39","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2025021410201190000_2025.02.11.637688v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.044"},{"key":"2025021410201190000_2025.02.11.637688v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.01.032"},{"key":"2025021410201190000_2025.02.11.637688v1.42","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-010-9779-6"},{"key":"2025021410201190000_2025.02.11.637688v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.103996"},{"key":"2025021410201190000_2025.02.11.637688v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705499114"},{"key":"2025021410201190000_2025.02.11.637688v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0658-4"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.02.11.637688","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:02:16Z","timestamp":1768464136000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.02.11.637688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":45,"URL":"https:\/\/doi.org\/10.1101\/2025.02.11.637688","relation":{},"subject":[],"published":{"date-parts":[[2025,2,12]]},"subtype":"preprint"}}